Oxidative damage to cells can occur in various lung diseases, cancer and inflammatory diseases, and in other conditions involving hypoxia or ischemia-reperfusion injury, such as organ transplantation. Such damage is caused by the accumulation of oxygen-free radicals and active oxidation species in cells, or by direct oxygen toxicity.
Antioxidants, such as superoxide dismutase (SOD), catalase (CAT), components of the glutathione redox system, antiproteases, and Vitamin E, can react with and neutralize free radicals and oxidation species, and are thus a key defense mechanism against oxidative damage in a cell. Therefore, such antioxidants (or other elements involved in the production of such antioxidants) are excellent targets for methods of treating or preventing oxidative damage.
An important endogenous cellular antioxidant is manganese superoxide dismutase (MnSOD). MnSOD is a mitochondrial enzyme which dismutates potentially toxic superoxide radical into hydrogen peroxide and dioxygen. This enzyme is critical for protection against cellular injury due to elevated partial pressures of oxygen. MnSOD can be induced by sublethal hyperoxia, hydrogen peroxide and cytokines such as TNF-.alpha. or IL-1. Hence, it has been proposed that MnSOD is regulated through a mechanism involving an oxidative stress response (i.e. is activated by oxidants). MnSOD reequilibrates cellular redox balance by diminishing oxidative stress.
Prior investigators have used various methods to attempt to treat and/or prevent oxidative damage. For instance, exogenously produced antioxidants, such as recombinant MnSOD or CAT, have been delivered directly to animals in which oxidative damage was induced. Delivery of exogenous antioxidants has met with limited success, however, and it is not clear that such treatment is effective clinically. Such methods have failed to deliver the antioxidant into the cell and, in the case of MnSOD, specifically to the mitochondrion where it is needed. Moreover, delivery of low molecular weight "mimetopes" of such compounds paradoxically increases toxicity when a cell's oxygen tension is increased.
Furthermore, at the time of the present invention, all described means of inducing endogenous production of an antioxidant, such as MnSOD, have involved administration of toxic substances such as bacterial endotoxin, bacterial toxic component lipid A, tumor necrosis factor (TNF), or interleukin-1 (IL-1). These inflammatory reagents can contribute to septic shock syndrome and adult respiratory distress syndrome (ARDS). Thus, there remains a need for methods by which antioxidants such as MnSOD can be safely and effectively administered or induced.
Despite research efforts directed toward the elucidation of cellular pathways involved in protection against oxidative damage, the mechanisms by which such pathways are induced and operate have not been clearly defined. Thus, there remains a need to identify effective clinical methods by which oxidative damage can be prevented or treated.